Tapping into the antitubercular potential of 2,5-dimethylpyrroles: A structure-activity relationship interrogation

Dorothy Semenya, Meir Touitou, Domiziana Masci, Camila Maringolo Ribeiro, Fernando Rogerio Pavan, Guilherme Felipe Dos Santos Fernandes, Beatrice Gianibbi, Fabrizio Manetti, Daniele Castagnolo*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

Abstract

An exploration of the chemical space around a 2,5-dimethylpyrrole scaffold of antitubercular hit compound 1 has led to the identification of new derivatives active against Mycobacterium tuberculosis and multidrug-resistant clinical isolates. Analogues incorporating a cyclohexanemethyl group on the methyleneamine side chain at C3 of the pyrrole core, including 5n and 5q, exhibited potent inhibitory effects against the M. tuberculosis strains, substantiating the essentiality of the moiety to their antimycobacterial activity. In addition, selected derivatives showed promising cytotoxicity profiles against human pulmonary fibroblasts and/or murine macrophages, proved to be effective in inhibiting the growth of intracellular mycobacteria, and elicited either bactericidal effects, or bacteriostatic activity comparable to 1. Computational studies revealed that the new compounds bind to the putative target, MmpL3, in a manner similar to that of known inhibitors BM212 and SQ109.

Original languageEnglish
Article number114404
JournalEUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume237
DOIs
Publication statusPublished - 5 Jul 2022

Keywords

  • Antimicrobial resistance
  • Antimycobacterial
  • MDR-TB
  • Pyrrole
  • SAR
  • Tuberculosis

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